Hope Center Member publications

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Naturalistic driving measures of route selection associate with resting state networks in older adults(2022) Scientific Reports, 12 (1), art. no. 6486, . 

Wisch, J.K.a , Roe, C.M.a , Babulal, G.M.a d e , Metcalf, N.a , Johnson, A.M.f , Murphy, S.a , Hicks, J.a , Doherty, J.M.a , Morris, J.C.a c , Ances, B.M.a b c

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities. © 2022, The Author(s).

Centrosome-dependent microtubule modifications set the conditions for axon formation(2022) Cell Reports, 39 (3), art. no. 110686, . 

Meka, D.P.a , Kobler, O.b , Hong, S.a , Friedrich, C.M.a , Wuesthoff, S.a , Henis, M.a c , Schwanke, B.a , Krisp, C.d , Schmuelling, N.a , Rueter, R.a , Ruecker, T.a , Betleja, E.e , Cheng, T.e , Mahjoub, M.R.e , Soba, P.f g , Schlüter, H.d , Fornasiero, E.F.h , Calderon de Anda, F.a

AbstractMicrotubule (MT) modifications are critical during axon development, with stable MTs populating the axon. How these modifications are spatially coordinated is unclear. Here, via high-resolution microscopy, we show that early developing neurons have fewer somatic acetylated MTs restricted near the centrosome. At later stages, however, acetylated MTs spread out in soma and concentrate in growing axon. Live imaging in early plated neurons of the MT plus-end protein, EB3, show increased displacement and growth rate near the MTOC, suggesting local differences that might support axon selection. Moreover, F-actin disruption in early developing neurons, which show fewer somatic acetylated MTs, does not induce multiple axons, unlike later stages. Overexpression of centrosomal protein 120 (Cep120), which promotes MT acetylation/stabilization, induces multiple axons, while its knockdown downregulates proteins modulating MT dynamics and stability, hampering axon formation. Collectively, we show how centrosome-dependent MT modifications contribute to axon formation. © 2022 The Author(s)

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Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders(2022) Cell Reports Medicine, 3 (4), art. no. 100607, . 

Gendron, T.F.a b , Heckman, M.G.c , White, L.J.c , Veire, A.M.a , Pedraza, O.d , Burch, A.R.e , Bozoki, A.C.f , Dickerson, B.C.g , Domoto-Reilly, K.h , Foroud, T.i , Forsberg, L.K.j , Galasko, D.R.k , Ghoshal, N.l m , Graff-Radford, N.R.e , Grossman, M.n , Heuer, H.W.o , Huey, E.D.p q , Hsiung, G.-Y.R.r , Irwin, D.J.s , Kaufer, D.I.f , Leger, G.C.k , Litvan, I.k , Masdeu, J.C.t , Mendez, M.F.u v , Onyike, C.U.w , Pascual, B.t , Ritter, A.x , Roberson, E.D.y , Rojas, J.C.o , Tartaglia, M.C.z , Wszolek, Z.K.e , Rosen, H.o , Boeve, B.F.j , Boxer, A.L.o , Appleby, B.S.aa , Barmada, S.aa , Bordelon, Y.aa , Botha, H.aa , Brushaber, D.aa , Clark, D.aa , Coppola, G.aa , Darby, R.aa , Devick, K.aa , Dickson, D.aa , Faber, K.aa , Fagan, A.aa , Fields, J.A.aa , Gavrilova, R.aa , Geschwind, D.aa , Goldman, J.aa , Graff-Radford, J.aa , Grant, I.aa , Jones, D.T.aa , Kantarci, K.aa , Kerwin, D.aa , Knopman, D.S.aa , Kornak, J.aa , Kremers, W.aa , Lapid, M.aa , Lago, A.L.aa , Ljubenkov, P.aa , Lucente, D.aa , Mackenzie, I.R.aa , McGinnis, S.aa , Mester, C.aa , Miller, B.L.aa , Pressman, P.aa , Rademakers, R.aa , Ramanan, V.K.aa , Ramos, E.M.aa , Rankin, K.P.aa , Rao, M.aa , Rascovsky, K.aa , Savica, R.aa , Seeley, W.aa , Staffaroni, A.M.aa , Syrjanen, J.aa , Taylor, J.aa , VandeVrede, L.aa , Weintraub, S.aa , Wong, B.aa , Petrucelli, L.a b , ALLFTD consortiumab

AbstractFrontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations. © 2022 The Author(s)

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High-speed multi-parametric photoacoustic microscopy of cerebral hemodynamic and metabolic responses to acute hemodilution(2022) Optics Letters, 47 (8), pp. 1988-1991. 

Wang, Y.a b c , Zhong, F.a d , Sun, N.a d , Xu, Z.a c , Li, J.e , Liu, Q.c , Li, Z.b c , Zuo, Z.e , Hu, S.a d

AbstractThe ability of hemodilution to improve vascular circulatory impairment has been demonstrated. However, the effects of acute hemodilution on cerebral hemodynamics and oxygen metabolism have not been assessed at the microscopic level, due to technical limitations. To fill this void, we have developed a new, to the best of our knowledge, photoacoustic microscopy system, which enables high-speed imaging of blood hemoglobin concentration, oxygenation, flow, and oxygen metabolism in vivo. The system performance was examined in both phantoms and the awake mouse brain. This new technique enabled wide-field (4.5×3 mm2) multi-parametric imaging of the mouse cortex at 1 frame/min. Narrowing the field of view to 1.5×1.5 mm2 allowed dynamic imaging of the cerebral hemodynamic and metabolic responses to acute hypervolemic hemodilution at 6 frames/min. Quantitative analysis of the hemodilutioninduced cerebrovascular responses over time showed rapid increases in the vessel diameter (within 50-210 s) and blood flow (50-210 s), as well as decreases in the hemoglobin concentration (10-480 s) and metabolic rate of oxygen (20-480 s) after the acute hemodilution, followed by a gradual recovery to the baseline levels in 1440 s. Providing comprehensive insights into dynamic changes of the cerebrovascular structure and function in vivo, this technique opens new opportunities for mechanistic studies of acute brain diseases or responses to various stimuli. © 2022 Optica Publishing Group.

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A Multivariate Functional Connectivity Approach to Mapping Brain Networks and Imputing Neural Activity in Mice(2022) Cerebral cortex (New York, N.Y. : 1991), 32 (8), pp. 1593-1607.

Brier, L.M.a , Zhang, X.b , Bice, A.R.a , Gaines, S.H.a , Landsness, E.C.c , Lee, J.-M.c , Anastasio, M.A.b , Culver, J.P.a d e f

AbstractTemporal correlation analysis of spontaneous brain activity (e.g., Pearson “functional connectivity,” FC) has provided insights into the functional organization of the human brain. However, bivariate analysis techniques such as this are often susceptible to confounding physiological processes (e.g., sleep, Mayer-waves, breathing, motion), which makes it difficult to accurately map connectivity in health and disease as these physiological processes affect FC. In contrast, a multivariate approach to imputing individual neural networks from spontaneous neuroimaging data could be influential to our conceptual understanding of FC and provide performance advantages. Therefore, we analyzed neural calcium imaging data from Thy1-GCaMP6f mice while either awake, asleep, anesthetized, during low and high bouts of motion, or before and after photothrombotic stroke. A linear support vector regression approach was used to determine the optimal weights for integrating the signals from the remaining pixels to accurately predict neural activity in a region of interest (ROI). The resultant weight maps for each ROI were interpreted as multivariate functional connectivity (MFC), resembled anatomical connectivity, and demonstrated a sparser set of strong focused positive connections than traditional FC. While global variations in data have large effects on standard correlation FC analysis, the MFC mapping methods were mostly impervious. Lastly, MFC analysis provided a more powerful connectivity deficit detection following stroke compared to traditional FC. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. 

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Functional Connectivity of the Developing Mouse Cortex(2022) Cerebral cortex (New York, N.Y. : 1991), 32 (8), pp. 1755-1768. 

Rahn, R.M.a b c , Brier, L.M.a , Bice, A.R.a , Reisman, M.D.d , Dougherty, J.D.b c , Culver, J.P.a d e

AbstractCross-sectional studies have established a variety of structural, synaptic, and cell physiological changes corresponding to critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex at 5 developmental timepoints beginning at postnatal day 15 (P15) and ending in early adulthood at P60. Calcium FC displayed coherent functional maps as early as P15, and FC significantly varied in connections between many regions across development, with the developmental trajectory’s shape specific to the functional region. Evaluating 325 seed-seed connections, we found that there was a significant increase in FC between P15 and P22 over the majority of the cortex as well as bilateral connectivity and node degree differences in frontal, motor, and retrosplenial cortices after P22. A rebalancing of inter- and intrahemispheric FC and local-distal FC dominance was also observed during development. This longitudinal developmental calcium FC study therefore provides a resource dataset to the field and identifies periods of dynamic change which cross-sectional studies may target for examination of disease states. © The Author(s) 2021. Published by Oxford University Press. All rights reserved.

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Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials(2022) Frontiers in Immunology, 13, art. no. 852563, . 

Ziemssen, T.a , Arnold, D.L.b c , Alvarez, E.d , Cross, A.H.e , Willi, R.f , Li, B.g , Kukkaro, P.f , Kropshofer, H.f , Ramanathan, K.f , Merschhemke, M.f , Kieseier, B.f , Su, W.g , Häring, D.A.f , Hauser, S.L.h , Kappos, L.i j , Kuhle, J.i j

AbstractObjective: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). Background: Previous post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. Design/Methods: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. Results: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, −0.32% vs. −0.24%, p=0.044, and teriflunomide, −0.43% vs. −0.29%, p=0.002), thalamic volume (−0.56% vs. −0.31%, p=0.047 and −0.94% vs. −0.49%, p<0.001), and WM volume (−0.30% vs. −0.19%, p=0.083 and −0.38% vs. −0.18%, p=0.003) but not of cGM volume (−0.39% vs. −0.32%, p=0.337 and −0.49% vs. −0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. Conclusion: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients. Copyright © 2022 Ziemssen, Arnold, Alvarez, Cross, Willi, Li, Kukkaro, Kropshofer, Ramanathan, Merschhemke, Kieseier, Su, Häring, Hauser, Kappos and Kuhle.

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Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries(2022) Nature Aging, 2 (3), pp. 214-223. 

Chen, X.a , Liu, X.b , Koundal, S.b , Elkin, R.c , Zhu, X.d , Monte, B.b , Xu, F.d , Dai, F.e , Pedram, M.b , Lee, H.b , Kipnis, J.f , Tannenbaum, A.a g , Van Nostrand, W.E.d , Benveniste, H.b h

AbstractCerebral amyloid angiopathy (CAA) is a common disease in older adults that contributes to dementia1–3. In CAA, amyloid beta (Aβ) is deposited along either capillaries (type 1) or vessel walls (type 2)4, with the underlying pathophysiology incompletely understood5. Here, we developed imaging and analysis tools based on regularized optimal mass transport (rOMT) theory6,7 to characterize cerebrospinal fluid (CSF) flow dynamics and glymphatic transport in a transgenic CAA type 1 rat model. We discovered that, in CAA, CSF moves more rapidly along the periarterial spaces that serve as influx routes to the glymphatic system. The observation of high-speed CSF flow currents in CAA was unexpected given the build-up of microvascular Aβ. However, velocity flux vector analysis revealed that CSF currents in CAA are partly diverted away from the brain, resulting in overall decreased glymphatic transport. Imaging at the neck showed that drainage to the deep cervical lymph nodes occurs along the carotid arteries and is time delayed in CAA, implying that upstream connections to the meningeal lymphatics were altered. Based on our findings we propose that, in CAA, both glymphatic transport and lymphatic drainage are compromised and that both systems represent therapeutic targets for treatment of CAA-related cognitive decline and dementia. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Couto, B.a , Martinez-Valbuena, I.b , Lee, S.b , Alfradique-Dunham, I.c , Perrin, R.J.d , Perlmutter, J.S.e , Cruchaga, C.f , Kim, A.b , Visanji, N.a b , Sato, C.b , Rogaeva, E.b , Lang, A.E.a , Kovacs, G.G.a b g hProtracted course progressive supranuclear palsy(2022) European Journal of Neurology

AbstractBackground and purpose: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). Methods: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. Results: We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. Conclusions: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation. © 2022 European Academy of Neurology.

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Posted on May 2, 2022
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